6-oxo-PGF(1 alpha)and 8-epi-PGF(2 alpha)in the arterial wall layers of various species: a comparison between intact and atherosclerotic areas.

PGI(2)and 8-epi-prostaglandin(PG)F(2 alpha)are antagonizing compounds. For both a key role in vascular pathology has been hypothesized. The isoprostane 8-epi-PGF(2 alpha)and the stable derivative of PGI(2), 6-oxo-PGF(1 alpha)were determined immunologically in the arterial wall of various species including humans. Human arterial tissue contained the highest amounts of 8-epi-PGF(2 alpha)and synthesized the lowest PGI(2). A significant negative correlation between 8-epi-PGF(2 alpha)and 6-oxo-PGF(1 alpha)was observed. Atherosclerotic segments showed significantly higher 8-epi-PGF(2 alpha)and lower 6-oxo-PGF(1 alpha). 8-epi-PGF(2 alpha)in the intima was higher than in the media, the highest amounts being found in foam-cell rich areas. Synthetic (activated) smooth muscle cells were associated with an enhanced 8-epi-PGF(2 alpha)as well as 6-oxo-PGF(1 alpha). Tissue samples derived from smokers contained more 8-epi-PGF(2 alpha)and produced less PGI(2). The by far highest 8-epi-PGF(2 alpha)/6-oxo-PGF(1 alpha)ratio was found in foam cell rich areas. Similar findings were obtained in rabbit and in minipig arteries. The total 8-epi-PGF(2 alpha)/6-oxo-PGF(1 alpha)ratio is low in normal tissue, increases significantly in an active atherosclerotic process and seems to be even further increased in an inactive atherosclerotic process. These findings are providing an information on the extent of oxidation injury at various sites of different types of atherosclerotic process.

Association of lipoprotein(a), prostaglandin I(2)--synthesis stimulating plasma factor, biological half-life of prostaglandin I(2)and high-density lipoproteins in HIV-1 infection of different stages.

Patients with human immunodeficiency virus show increased atheroembolism and premature arterial events (stroke, myocardial infarction), but no increased venous thromboembolism. This paper describes an association of elevated lipoprotein(a), a decreased prostaglandin I(2)(PGI(2)) synthesis stimulating plasma factor, diminished PGI(2)-stability in plasma and decreased high-density lipoprotein-cholesterol and apolipoprotein A. It is unclear to what extent these biochemical findings represent an acute phase reaction only or a disturbance in the prostaglandin system. Definitely, they are resulting in severe hemostatic imbalance decreasing local PGI(2)-availability with a dramatic reduction in the cytoprotective capacity favouring the onset of premature arterial events seen in some of the patients.

[Unaltered homocysteine levels during simvastatin therapy]. / Unverändertes Homocystein unter Simvastatin-Therapie.

Homocysteinemia is regarded as a risk factor for vascular disease. Several risk factors and diseases, but also various drugs, amongst them some lipid lowering medications, have been shown to increase plasma homocysteine concentrations. We therefore assessed the influence of simvastatin on plasma homocysteine levels in 57 patients suffering from severe familial heterozygous hypercholesterolemia. After 1, 3 and 6 months of simvastatin therapy plasma homocysteine levels did not show any change compared to the levels before therapy. Males had typically higher homocysteine levels than females and concentrations in smokers were in most subgroups significantly higher than in non-smokers. No difference in patients taking either 20 or 40 mg simvastatin was apparent and no correlation to the lipid lowering action was found. These findings indicate that in contrast to a number of other lipid lowering agents, simvastatin does not affect plasma homocysteine levels.

Semotiadil, a new calcium antagonist, is a very potent inhibitor of LDL-oxidation.

The influence of semotiadil, a novel benzothiazine calcium antagonist on in-vitro copper-, 2,2àzo-bis-(2,4 dimethylvaleronitrile)[AMVN]-, and 2,2àzo-bis-(2-amidinopropane) [AAPH]-induced low-density lipoprotein (LDL) oxidation was assessed. The following parameters were measured: lag-time of oxidation, maximal rate of oxidation, dienes formed through continuous monitoring of developing conjugated dienes, thiobarbituric acid reactive substances, isoprostane(8-iso-PGF2alpha)-generation and relative electrophoretic mobility. The effect was compared with nifedipine, amlodipine and diltiazem. Besides the influence on isoprostane (8-iso-PGF2alpha)-generation where nifedipine was equipotent with semotiadil at 10(-3) M, semotiadil demonstrated a strong and significant effect in attenuating the indicated indices of LDL-oxidation, in particular, dose-dependently (10(-3) M to 10(-7) M). These results indicate that semotiadil may have the strongest antioxidant activity on LDL among the calcium antagonists examined.

The economy class syndrome--a survey of 19 cases.

BACKGROUND: Thromboembolic events during or immediately after long-distance flights (economy class syndrome--ECS) are gaining more importance due to the rapidly increasing number of flights. Systematic data on haemostatic parameters in these patients are not available yet. PATIENTS AND METHODS: We were therefore analyzing the anamnestic, laboratory and clinical findings in 19 patients (17 males, 2 females, aged 33-75 years) with the final clinical diagnosis ECS. RESULTS: Symptoms commenced either immediately or up to 93 hours after disembarkation (mean 42.3 hours). In the great majority (84.2%) myocardial infarction was the initial diagnosis. No defect in the coagulation and/or prostaglandin system was discovered in either of the patients. Prevalence of smoking (26.3%) was even lower than in the normal population. No predisposing factors were found. Apparent anamnestic similarities were flu and fever (47.4%) while 4 of the patients (26.3%) had severe diarrhoea and dehydration before the flight. Almost all the patients (78.9%) were drinking alcohol during the flight and not actively moving their legs (84.2%). ECS occurred also in business and first class passengers. CONCLUSION: Surprisingly the onset of ECS is definitely not associated with haemostatic defects and not necessarily associated with the clinical risk factors reported.

Influence of radiation synovectomy on articular cartilage, synovial thickness and enhancement as evidenced by MRI in patients with chronic synovitis.

UNLABELLED: Radiation synovectomy is a safe and effective treatment for chronic synovitis that is refractory to the repetitive, intra-articular application of glucocorticosteroids in patients with rheumatoid or seronegative arthritis. Short-term and long-term effects of radiation synovectomy on articular cartilage, synovial enhancement and thickness were assessed in a prospective, clinical trial by MRI. METHODS: Thirteen patients (mean age 39+/-13 y) were treated with a median activity of 8.4 GBq 165Dy ferric hydroxide, a radionuclide with favorable physical properties and a well-documented clinical safety and efficacy profile. MRI was performed on a 1.5-T MR unit using a circular polarized knee coil. RESULTS: After a mean observation period of 13 mo, a marked reduction in synovial enhancement was observed in 10 patients. The mean reduction in baseline synovial thickness (mean 7.6+/-3.0 mm) was 24% (P = 0.03) at 1 wk and 42% (P = 0.01) about 1 y after treatment, respectively. Clinically, 9 of 13 patients (69%) exhibited persistent response to radiation synovectomy. The local clinical score, as defined by the reduction in pain, pannus, joint effusion and by the increase in the range of motion, improved significantly (P = 0.01), from a median of 7 (range 4-10) to a median of 2 (range 0-9). One year after treatment, changes in the local clinical score were related to the decrease in synovial enhancement in MRI (r = 0.7, P = 0.008, n = 12). There were no persistent adverse effects, nor was there evidence for any severe radiation-induced damage to the articular cartilage. On later follow-up images, the structure of the articular cartilage remained unaltered in all but 3 patients, who had new, superficial erosions most likely attributed to an active disease with persistence of inflammation. CONCLUSION: This study suggests that radiation synovectomy with 165Dy-ferric hydroxide is effective in terms of reducing chronic synovitis without causing detectable harm to the articular cartilage, as shown by MRI.

6-Oxo-PGF1alpha and 8-epi-PGF2alpha in human atherosclerotic vascular tissue.

Isoprostanes are a new family of compounds generated by the free radical catalyzed action on arachidonic acid. Formed during oxidation they have been claimed to be a reliable indicator of in vivo oxidation injury. We assessed the amount of 8-epi-PGF2alpha in human surgical specimens as compared to PGI2 (via its stable metabolite 6-oxo-PGF1alpha), the major compound generated by vascular tissue. 8-epi-PGF2alpha is low in normal vascular tissue as is the 8-epi-PGF2alpha/6-oxo-PGF1alpha ratio. The vessels of smokers in general exhibited an increased 8-epi-PGF2alpha (r=0.82) and a decreased 6-oxo-PGF1alpha (r=0.71). The 8-epi-PGF2alpha/6-oxo-PGF1alpha ratio is, not significantly, increased in vessels derived from hyperlipidemics and hypertensives. These findings indicate that lipid peroxidation occurs within the human arterial wall as evidenced by 8-epi-PGF2alpha, probably further decreasing the synthesis of PGI2 and promoting atherogenic mechanisms.

Endothelial dysfunction, atherosclerosis and diabetes.

The prevalence of early and accelerated development of atherosclerosis associated with high morbidity and mortality is markedly increased among individuals with diabetes and hypertension. Although the link between diabetes and vascular disease is not fully understood, loss of the modulatory role of the endothelium could be implicated in the pathogenesis of diabetic vascular complications. Diabetes-associated pathophysiologic conditions in the endothelium are modifications of lipoproteins, formation of advanced glycation end-products and circulating lipoprotein immune complexes, alteration of the nitric oxide pathway, and elevated levels of homocysteine. The main goals in restoration of endothelial function are optimal glycemic control, lipid lowering, cessation of smoking, normalization of elevated blood pressure, improvement of the NO-status, antioxidants for scavenging free oxygen radicals, normalization of homocysteine levels, antagonizing the hyperinsulinaemia, and regulation of rheology, respectively haemostasis to physiological levels. There is abundant evidence that some pharmacological agents exert direct beneficial effects on endothelium, suggesting that at least part of their therapeutic action is associated with improvement in endothelial dysfunction. A number of new findings about endothelial dysfunction may have potential clinical relevance.

Unusual imaging of varicose veins after radiolabeling of autologous low-density lipoproteins.

LDL-radiolabeling with various isotopes (123I, 125I, 131I, 111In, 99mTc and 67Ga, among others) has been used for imaging the arterial wall, monitoring the LDL-kinetics and in particular to assess vascular surface lining and foam cell content. From 286 patients studied with 111In-LDL scintigraphy, only 9 patients presented clinical varicosis. In 2 of these 9 patients a predominant imaging of varicose veins has been shown with scintigraphy, while in the other 7 patients no positive scintigraphic imaging could be detected. In vitro and in vivo perfusion experiments did not reveal an explanation for this unusual results. The reason for that positive LDL-uptake into varicose veins is unknown. These findings indicate that localized LDL-uptake has to be interpreted carefully in order to avoid potential false positive results.

Isradipine lowers human arterial low density lipoprotein retention in vivo.

During the recent past it has been discussed that calcium antagonists may exert antiatherosclerotic actions at the vessel wall. Apolipoprotein B containing lipoproteins were isolated by immunoaffinity chromatography and radiolabeled with 123-iodine. The effect of 2 x 2.5 mg isradipine on the low density lipoproteins (LDL) entry into the carotid and femoral arteries of 12 hypertensive patients with primary hyperlipoproteinemia (total cholesterol >6.5 mmol/l [250 mg/dL) was examined. Cholesterol -1.7% (P< 0.05 664), high density lipoprotein (HDL) cholesterol +4.5% (P< 0.01 123), and LDL cholesterol -1% (P< 0.01 563) did not change, nor did any of the safety parameters. The types of entry kinetics reflecting vascular surface lining did not change while the LDL retention 20 h after tracer application was depressed by up to 23.5%. The data were comparable in the carotid and femoral artery segments, the significance level ranging up to 0.0009. These results indicate a decreased LDL retention in the arterial wall of hypertensive patients induced by isradipine. The clinical implications of the findings ought to be pursued in properly designed clinical trials.

Effect of isradipine on in-vivo platelet function.

In animal studies calcium channel blockers (CCB's) and especially isradipine, a second generation dihydropyridine, interrupt the sequence of events culminating in the formation of atherosclerotic lesions. The effect of 4 weeks isradipine treatment (5mg daily) on blood pressure and in-vivo platelet function (measured with 111Indium-oxine labeled autologous platelets) were investigated in a randomized, double-blind and placebo controlled trial in 40 patients with mild to moderate hypertension and scintigraphically diagnosed active atherosclerotic lesions of the carotid arteries. The average supine systolic/diastolic blood pressure was significantly reduced at the end of the treatment period in the isradipine group (group 1; p < 0.0001) but remained unchanged in the placebo group (group P). The heart rate was not significantly altered in either group. There were no serious side effects. The platelet uptake ratio (PUR) measured over the atherosclerotic region of the carotid artery on 4 consecutive days before and after treatment decreased significantly in group I from 1.20 to 1.15 (within groups: p < 0.0001) but remained unchanged in group P. Platelet survival increased significantly in group I (mean 5.70 hours, lower quartile 4.50, upper quartile 4.50 hours, within groups: p < 0.0001) and remained unchanged in group P. Isradipine has a beneficial effect on in-vivo platelet function as evidenced by a decreased platelet deposition on vascular lesion sites and an associated prolonged platelet survival in patients with hypertension and active atherosclerotic lesions.

Chloroquine minimizes sampling artefacts for radioimmunological determination of thromboxane B2 in plasma.

Chloroquine is known to inhibit platelet activation by various mechanisms including arachidonic acid liberation from membrane phospholipids. We therefore examined the influence of chloroquine in addition to the conventional EDTA/acetylsalicylic acid cocktail on thromboxane B2-plasma values. In 11 healthy volunteers the influence of venous occlusion, needle diameter and EDTA (+ acetylsalicylic acid + chloroquine) was examined. In 27 healthy adults, 51 patients with clinically manifested coronary heart disease as well as in 31 patients with peripheral vascular disease parallel samples drawn in the presence of chloroquine showed lower thromboxane B2 in all these three groups of patients, especially in conditions associated with platelet activation and high thromboxane B2-values. These findings suggest that the routine addition of 10 mM chloroquine to the conventional stabilization cocktail can strongly be recommended.

Antimitotic actions of vasodilatory prostaglandins--clinical aspects.

A variety of in-vitro antiatherosclerotic actions, among them those on vascular smooth muscle cells (mitotic activity, proliferation, extracellular matrix production), have been identified especially for PGE1 and PGI2, and proven in experimental animals. Ex-vivo data in humans are not yet available. We examined the effect of PGE1-, PGI2- and iloprost therapy of various duration (1-4 weeks) on smooth muscle cells (mitosis, proliferation, prostaglandin formation from exogenous and endogenous substrate) derived from vascular surgery samples. In-vivo PG-therapy decreases [3H]-thymidine incorporation as well as [35]S- and [14C]-proline uptake. These effects are dependent on the duration of treatment, PGE1 being trendwise more effective. Arachidonic acid conversion to PGI2 is significantly enhanced in activated smooth muscle cells of the plaque, both in the intima as well as in the media. Due to the activation of the gene for COX-2, the actual synthesis of PGI2 as well as the conversion rate to 6-oxo-PGF1 alpha are increased in activated smooth muscle cells, an effect being abolished by the PG's administered. It can thus be concluded that PG-therapy for advanced atherosclerosis seems to affect vascular smooth muscle cells beneficially, decreasing mitotic and proliferative activity as well as collagen and glycosaminoglycan synthesis. The somewhat less pronounced effect for PGI2 and iloprost could be explained by desensitization at the receptor level as preliminary findings suggest. This could become even more relevant if a long-term administrable stable (oral) analogue becomes available for routine therapy.