H. Sinzinger

Autologous low-density lipoprotein labelling allows characterization of human atherosclerotic lesions in vivo as to presence of foam cells and endothelial coverage

The monitoring of local vascular kinetics after injection of autologous radiolabelled low-density lipoprotein (LDL) allows characterization of human atherosclerotic lesions as to the presence of foam cells and the quality of endothelial coverage. The following evidence exists: (1) dynamic imaging reveals two types of visual LDL accumulation in the vascular bed, one increasing, becoming visible sometimes only as late as after 24 h, and the other one appearing very early on, but decreasing with time; (2) the accumulation of iodine-123 LDL or iodine-131 LDL in the vascular bed shows three major types of local kinetic curves, which correlate with scintigraphic findings; (3) the accumulation of radiolabelled LDL in the vascular bed of humans in vivo is similar to its uptake in de- and re-endothelialized vessels of experimental animals using 125I-LDL; (4) morphological control in endarteriectomy samples confirms the hypothesis that this promising new approach may for the first time allow the in vivo monitoring of preclinical lesions in humans.

Pentoxifylline enhances formation of prostacyclin from rat vascular and renal tissue

In 6 months old male Wistar rats 15 mg pentoxifylline/kg body weight were given intravenously in a single dose. The animals were sacrificed after 30, 60, 120 and 240 minutes respectively. It was confirmed that a single pentoxifylline administration enhanced prostacyclin generation by vascular and renal tissue samples, reaching its maximum 60 minutes after the treatment. The time course for PGI2-generation behaves differently in the tissues examined. It is concluded that the drug pentoxifylline might exert its beneficial role in the treatment of peripheral vascular disease at least in part by its influence on hemostatic balance at the endothelial-platelet interaction level.

Isradipine: A potent calcium blocker with beneficial effects on platelet function and vascular prostacyclin production

Calcium blockers inhibit platelet aggregation induced in vitro by various stimuli, such as ADP and collagen. In this study the in vitro effects of isradipine, a new dihydropyridine-derivative, and of nifedipine on platelet aggregation and malondialdehyde-production were tested. The lowest concentrations affecting ADP-induced platelet aggregation were 1.0 micrograms/ml isradipine and 12.5 micrograms/ml nifedipine. Both drugs exhibited an inhibitory action on malondialdehyde-production in concentrations 2 to 3 times lower than those affecting platelet aggregation. In vitro, PGI2-formation by rat aortic rings incubated with calcium blockers was increased in a dose-dependent manner. The lowest concentration of isradipine which increased PGI2-generation amounted 0.5 micrograms/ml. The corresponding value for nifedipine was 10 micrograms/ml. The findings demonstrate isradipine to be more potent than nifedipine in affecting in vitro platelet aggregation and enhancing PGI2-formation.

Nuclear medicine and atherosclerosis

Although the pathomechanisms of atherosclerosis are well known, their radioisotopic monitoring is still in its early childhood. The current radioisotope techniques are of only limited value for contributing to the clinical diagnosis of atherosclerosis. The limited reaction time of cellular blood constituents (platelets, monocytes) with the vascular surface at the injury site makes it very difficult to catch the point of injury. Lipoproteins excellently allow receptor imaging, while vascular monitoring is only of scientific interest at present. Labelling and subsequent imaging of components of the coagulation cascade have not succeeded so far, nor have attempts using unspecific labels such as porphyrin, polyclonal IgG and Fc fragments, for example. Preliminary evidence indicates that radioisotopic techniques may be of great benefit in the future in elucidating functional aspects of the disease, while they do not contribute to examining the stage and extent of atherosclerosis.

Effects of Exercise on Parameters of Blood Coagulation, Platelet Function and the Prostaglandin System

SummaryAcute exercise causes a temporary short lasting activation of blood coagulation, platelet function and the prostaglandin system, the extent of these alterations being significantly less pronounced in well trained athletes than in untrained persons. The reversal is also much faster in athletes, thus providing an underestimated indicator of the individual training status. Changes in platelet function and some plasma parameters of coagulation exhibit a significant correlation to base excess, pH and lactate. Immediately after acute exercise there is, therefore, an increased risk for acute thrombosis if an additional risk such as doping and/or smoking and/or contraceptive pill use is present. This risk is again higher in untrained than in well exercised persons. Patients with clinically manifest atherosclerosis (predominantly with risk factors) performing only occasionally anaerobic exercise are more likely to be at special risk. The overall response of the coagulation system, platelet function and prostaglandin system is significantly impaired. In contrast, regular exercise causes decreased activity of platelets and the coagulation system resulting in an improvement in haemostatic balance. As well as the psychological factors beneficially influencing the subjective feeling, it seems rather likely that the abovementioned mechanisms may be one factor underlying the decreased death rate from cardiovascular disease in persons performing regular physical activity.

Isradipine improves platelet function in hypertensives

SummaryThe effect of treatment for eight weeks with isradipine 1.25 mg twice daily for 4 weeks and thereafter 2.5 mg twice daily for 4 weeks on ex vivo platelet function was investigated in 10 male hypertensive patients, aged 51 (6.1) y.Systolic and diastolic blood pressure, platelet aggregation in response to ADP, serum thromboxane B2 and β-thromboglobulin levels were significantly decreased at rest before exercise ergometry, during exercise and at rest after exercise. The platelet count, platelet sensitivity and the plasma levels of 6-oxo-prostaglandin F1α were not affected by isradipine.It is concluded that a compound that lowers blood pressure and inhibits platelet activation may be of clinical benefit in the routine treatment of hypertension.

A double blind placebo controlled trial of intravenous prostacyclin (PGI2) in 108 patients with ischaemic peripheral vascular disease

108 patients with ischemic peripheral vascular disease were randomly allocated to receive infusion of either PGI2 (6 ng/kg/min over 8 hours daily for 5 consecutive days) or placebo in a double-blind manner. All patients had Stage II disease (Fontaine classification). One month after infusion the absolute and relative walking times were significantly (p less than 0.05) longer in the PGI2- than in the placebo-treated group. Patients were further classified as treatment responders or non-responders on the basis of increase of absolute and relative walking times. After one month 44% (24 out of 54) of the PGI2- and 15% (8 out of 54) of the placebo-treated patients were positive treatment-responders (p less than 0.01).

Ticlopidine and platelet function in healthy volunteers

The influence of a 4-weeks therapy with 500 mg ticlopidine daily on platelet function parameters was examined in 10 male healthy volunteers aged 20-33 years in order to extend the knowledge on the antiplatelet activity of this substance. Ticlopidine significantly (p less than 0.01) affected ex-vivo platelet aggregation induced by ADP and increased platelet sensitivity to the antiaggregatory action of PGI2. Generation of TXB2 from endogenous substrate during spontaneous clotting of blood (serum-TXB2), conversion of exogenous radiolabelled arachidonic acid into TXB2 and MDA-formation in isolated platelets were unaffected by the treatment. The TXB2-level in plasma of volunteers, however, was decreased, after administration of the drug. The diminished alpha-granule content liberation (beta-thromboglobulin: p less than 0.01; PDGF: p less than 0.01; PF4 not significant) indicates that ticlopidine induces a decrease in platelet activity. The beneficial effect on release reaction is not associated with a decrease in TXA2-formation. Our results demonstrate that ticlopidine inhibits platelet activity, especially the PDGF-release. These results confirm the value of this drug in the prevention of atherosclerosis and its thromboembolic complications.

Effect of prostaglandin E1 on low density lipoprotein apo-B-receptor binding in human, rat and swine liver in vitro

The effect of PGE1 on low density lipoprotein (LDL) apo-B-receptor binding was examined in human, rat and swine liver. Autologous LDL (for humans and swines) and homologous LDL (for rats) were isolated by ultracentrifugation and labelled with 123I using Iodogen followed by purification with dialysis. LDL-concentrations of 0.1-6 micrograms protein/ml were used for direct binding assays investigating the specific binding of labelled LDL in presence of increasing PGE1-concentrations (100 pM to 100 microM). In separate experiments the effect of PGE1 on displacement of specifically bound 123I-LDL by unlabelled ones was studied. The binding capacities estimated by Scatchard analysis were similar for human and rat liver LDL-apo-B-receptor binding, however, swine liver exhibited a significantly (p less than 0.001) lower binding capacity for 123I-LDL. PGE1 significantly (p less than 0.01-0.001) increased the amount of 123I-LDL specifically bound to the liver apo-B-receptors and the binding affinity in all liver preparations of the 3 species in a dose-dependent manner. PGE1 also significantly increased competition of unlabelled LDL for 123I-LDL bound to its specific apo-B-receptors in a dose-dependent manner (p less than 0.01-0.001) with an ED50 of 123 +/- 64 nM for human liver, 901 +/- 102 nM for rat liver obtained during anaesthesia, 74 +/- 23 nM for rat liver obtained after decapitation and 941 +/- 121 nM for swine liver. In human liver iloprost (ED50 = 876 +/- 53 nM) and PGI2 (ED50 = 52 +/- 12 microM) were less effective than PGE1, PGE2 had no effect on LDL-induced competition. It is concluded that PGE1 renders LDL more sensitive for apo-B-receptor binding suggesting a potential hypolipidemic action of PGE1.

Prostaglandin E1 decreases the low‐density‐lipoprotein entry into rabbit arterial wall

1 In 72 male rabbits fed a 1% cholesterol supplemented diet the effect of a 4 weeks daily infusion of prostaglandin E1 (PGE1, 20 μg kg−1min−1 over 2 h) on [125I]‐low density lipoprotein (LDL) accumulation (10 μCi; 0.5 mg protein ml−1) was examined versus sham‐treatment after removal of the endothelium of the abdominal aorta by a Fogarthy catheter. 2 The uptake of [125I]‐LDL was significantly (P < 0.01) higher in endothelium‐free aortic segments (showing the highest peak maximum at around 12 h after 125I‐injection) as compared to aortic segments with endothelium intact (showing the lowest uptake of [125I]‐LDL with the peak maximum at 48 h, last control time). Segments with the endothelium restored showed a similar LDL‐retention curve to segments with endothelium however, being again significantly (P < 0.01) higher. 3 PGE1‐treatment caused reduction in LDL‐accumulation, being significantly (P < 0.001) pronounced in segments without endothelium and in segments with endothelium restored. 4 The findings indicate a beneficial effect of PGE1 in lipid metabolism by decreasing the LDL‐influx into the arterial wall in‐vivo.