Eicosanoid production and lymphatic responsiveness in human cigarette smokers compared with non-smokers.

Leg lymphatic segments were isolated from 10 patients (4 cigarette smokers and 6 non-smokers) undergoing conventional lymphography. Prostaglandin (PG) levels and PG synthesis in the lymphatics and in a variety of body fluids and the effects of eicosanoids on lymphatic contractility were determined. Leg lymphatics from 4 smokers generated less PGI2 and contained more 8-epi-PGF2 alpha when compared with leg lymphatics in 6 non-smokers. Similarly, levels of 8-epi-PGF2 alpha in smokers compared with non-smokers were higher in plasma (28.6 cf 19.7 pg/ml), leg lymph (146.7 cf 65.3 pg/ml), serum (299.0 cf 204.1 pg/ml), and urine (473.4 cf 241.0 pg/mg creatinine). Lymphatics from smokers also showed a higher contractile response, less 14C-arachidonic acid conversion to PGI2 and less PGI2-formation with various stimuli compared with non-smokers. Together these findings suggest that smoking induces oxidation injury, promotes altered (iso-)eicosanoid production and impacts on the function and dysfunction of peripheral lymphatics under normal circumstances and in a variety of clinical disorders.

Eicosanoid generation and responsiveness of human lymphatics in hyperlipoproteinemia.

In this work, the oxidation injury in hyperlipoproteinemia (HLP) was determined by measuring the isoprostane 8-epi-prostaglandin (PG) F2alpha in human lymphatics, lymph fluid, plasma, serum and urine. Lymphatics from 6 patients with HLP generated less PGI2 and contained more 8-epi-PGF2alpha as compared to 6 normolipemics without risk factors. Likewise, plasma (29.3 vs 19.7 pg/ml), lymph fluid (137.3 vs 65.3 pg/ml), serum (286.7 vs 204.1 pg/ml) and urinary (360.8 vs 241.0 pg/mg creatinine) values of 8-epi-PGF2alpha in HLP (as compared to normolipemics) were significantly elevated. Lymphatics from HLP showed an enhanced contractile response, less 14C-arachidonic acid conversion to PGI2 and less PGI2-formation upon various stimuli compared to normolipemics of comparable age. These findings indicate that HLP-induced oxidation injury, resulting in an altered (iso-)eicosanoid production and function, may also significantly affect (patho-) physiology of lymphathics.

Levels of eicosanoids (6-oxo-PGF1 alpha and 8-epi-PGF2 alpha) in human and porcine lymphatics and lymph.

Prostaglandin (PG)I2 is the primary eicosanoid synthesized by human lymphatics and 8-epi-PGF2 alpha, an isoprostane formed during free radical catalyzed peroxidation, is the most potent stimulator of lymphatic contraction tested thus far. We now examine the respective concentrations in the lymphatic wall of both human and porcine lymphatics and lymph fluid using specific immunoassays. Although both compounds are detectable in the lymphatic wall and lymph fluid, PGI2- (via its main metabolite 6-oxo-PGF1 alpha) is greater in the lymphatic wall whereas 8-epi-PGF2 alpha dominates in lymph fluid. Because inflammation is associated with oxidative injury, which in turn stimulates release of isoprostane, eicosanoid derivatives may modulate lymphatic tone during acute tissue reaction.

Isoprostane 8-epi-prostaglandin F2 alpha is a potent contractor of human peripheral lymphatics.

Isoprostanes are products of free radical-catalyzed peroxidation and 8-epi-prostaglandin (PG) F2 alpha is the most important vasomodulator of this group of compounds. In human lower leg lymphatics isolated from 5 different patients without a smoking history or hyperlipidemia, 8-epi-PGF2 alpha stimulated in vitro contraction more strongly than the thromboxane receptor agonist U46619. Other isoprostanes (8-epi-PGE1, 8-epi-PGE2) had only limited lymphatic contractile potency. These data suggest a potentially relevant role for epi-8-PGF2 alpha in facilitating lymph transport especially in conditions of inflammation.

[Differential diagnosis and therapy of bradycardic arrhythmias]. / Differentialdiagnose und Therapie bradykarder Rhythmusstörungen.

The most important symptoms in bradycardia are vertigo, dizziness and syncopy due to diminished cerebral blood sypply. Cardial symptoms are cardiac insufficiency and angina pectoris. By means of ECG, especially Holter-ECG, carotid sinus massage, atropin test and invasive methods (atrial stimulation, His-bundle ECG) sinu-nodal dysfunction, carotid sinus syndrome, bradyarrhythmia absoluta and AV-block can be diagnosed. Pharmacological treatment is only useful in acute situations. For symptomatic bradyarrhythmias the implantation of a Pacemaker is the therapy of choice. Individual treatment of the various types of bradyarrhythmia and the patients special needs is possible through the evolution of pacemaker technology.

Determinants of subsidiary ventricular pacemaker suppression in man.

To investigate the relative contribution of the duration and rate of overdrive to subsidiary ventricular pacemaker suppression, in six patients with complete heart block after His-bundle ablation, ventricular overdrive stimulation studies were performed. The studies, which were spread over a mean follow-up period of 745 days, were carried out invasively with a temporary lead (one patient) as well as noninvasively with the implanted pacemakers and chest wall inhibition (five patients). The overdrive pacing rate was increased in steps of 10 beats/min, and the pacing duration was 15, 30, 60, 90, and 120 seconds at each level. A recovery period of 2 minutes was allowed after each overdrive stimulation. Incremental ventricular overdrive stimulation at increasing pacing durations consistently caused progressive suppression of ventricular impulse formation. Nonparametric variance analysis demonstrated a significant (P less than 0.0001) influence of both the pacing rate and duration on ventricular recovery time. Nonlinear regression showed an exponential increase in recovery time with incremental pacing rate and a biphasic increase in recovery time with incremental pacing duration. Beyond a pacing duration of 60 seconds ventricular impulse suppression was primarily dependent upon the pacing rate. A nonlinear regression model was applied to predict the number of beats required for return of the escape rhythm toward prepacing control values. The predicted maximum mean number of beats was 15.4 +/- 5.9 and independent of the rate and duration of pacing, although, the initial temporary instability of the escape rhythm was directly related to the degree of overdrive.

[Recanalization of an iliac artery occlusion from the contralateral side using "low-speed rotational angioplasty"]. / Die Eröffnung eines Iliacaverschlusses von der kontralateralen Seite mittels "Low-speed rotational angioplasty".

This paper demonstrates the applicability of "low-speed rotational angioplasty" in antegrade direction for recanalization of the common iliac artery. After recanalization, a 4-mm PTCA balloon was used to dilate in antegrade direction using a PTCA exchange wire. After 5 weeks the femoral artery could be punctured and a residual stenosis dilated in retrograde direction.

Platelet lipoxygenase defect (Wien-Penzing defect) in two patients with myocardial infarction.

In 2 male patients (35 and 38 years) presenting with myocardial infarction an abnormal conversion of exogenous 14C-arachidonic acid by the patients' platelets, incubated in vitro, was observed. Neither patient's platelets showed evidence of a lipoxygenase pathway. Platelet thromboxane formation from exogenous and endogenous substrate was high, while the platelet aggregation responses were normal. A myeloproliferative syndrome was excluded by bone marrow puncture. Similar defects have only been described so far in patients with myeloproliferative syndrome. This defect may be causative for the onset of clinical thrombotic events. It is speculative whether in vivo therapy with r-IFN alpha 1c might be able to eradicate the pathological platelet clone.

Digital vascular reactivity in patients on haemodialysis treated with human recombinant erythropoietin.

Digital vascular reactivity was determined in 12 normotensive patients on chronic hemodialysis without a history of Raynaud's phenomenon before and after partial correction of anaemia with human recombinant erythropoietin (rHuEPO): apparent finger systolic pressures and finger skin temperatures were recorded at rest, after local cooling, and following 5 minutes rewarming time. Finger systolic pressures remained constant during the whole test, pre and post rHuEPO therapy. The decrease in finger skin temperatures after cold provocation as well as the rewarming behaviour after cooling were normal in both examinations. The present data indicate that treatment with EPO does not interfere with digital arterial reactivity in normotensive patients on haemodialysis.

Successful therapy of the prostaglandin defect "Wien-Hietzing" (lack of platelet high-affinity binding sites for prostaglandin I2).

Some years ago we detected a lack of platelet high-affinity PGI2 binding sites in a 10 year-old girl who presented to the outpatient unit with clinical symptoms and signs of acute popliteal artery occlusion. We named this new defect in the prostaglandin system "Wien-Hietzing". Acute surgery was successful. On the basis of earlier findings that aspirin is able to sensitize platelets to the action of PGI2 and produce beneficial changes in platelet sensitivity, we decided to treat this girl with a daily dosage of 20 mg aspirin orally. Repeated control examinations during the total follow-up period of about 6 years revealed normalized platelet sensitivity and normalized receptor behaviour. The girl is symptom-free to date. It is concluded that this prostaglandin defect may be successfully treated with long-term, low-dose aspirin administration.

Additive benefit of PGI2 and PGE1 (via different mechanisms?) on inhibition of activation of human vascular smooth muscle cells?

It seems likely that the antiplatelet action of antiaggregatory prostaglandins (PGE1, PGI2) is not the pivotal mechanism of action involved in clinical improvement of peripheral vascular disease. Based upon earlier results that both of these agents may have a certain effect on proliferation of vascular smooth muscle cells, we approached that question of an "optimal therapeutic regimen" going one step further. Patients having to undergo amputation were given a randomized "last choice" therapy with either PGI2 (once or twice a day, 6 h, 5 ng/kg/min i.v.), PGE1 (once or twice a day, 1 ng/kg/min i.a.) or a combination of both with a 6 h interval in between for 5 consecutive days. The ones who underwent surgery had a pathomorphological examination of vascular segments removed during amputation. The counting of activated smooth muscle cells indicates a significant drop induced by both of the PG's alone. A second infusion a day with the same compound, however, did not induce a further decrease in the activation state. In contrast administering the complimentary PG caused a comparable, significant decrease (p less than 0.01) in activation of smooth muscle cells in the intima and the media as well. It thus seems, that different mechanisms may be involved inducing additive therapeutic benefit. PGI2 is hypothesised to act predominantly by blocking PDGF-release and interference with PDGF, whereas PGE1 may have a more direct vascular action. From these findings, as well as the beneficial clinical results to be reported elsewhere, a combined therapy by the infusion scheme used may be the optimal one for a PG-therapy at the moment, based upon platelet and smooth muscle cell action.

Beneficial effect of long-term PGE1-treatment in left ventricular heart failure.

Five male patients aged 34-47 years with congestive heart failure showed an improvement of left ventricular ejection fraction (LVEF) at rather low PGE1-doses (10-30 ng/kg/min) without affecting blood pressure or heart rate. LVEF was estimated by means of radionuclide ventriculography (RNV) prior to and during i.v.-infusion of PGE1 at increasing dose rates (10-100 ng/kg/min). Therefore, we administered to these responders PGE1 at a rate of 20 ng/kg/min i.v. continuously on a long-term basis by means of a portable infusion pump. Until up to 4 months the remarkable benefit in LVEF induced by PGE1 was still present to a comparable extent in all the patients. No rebound desensitization phenomenon occurred either on platelet activity or on LVEF. PGE1, via a more practical route of application or by a stable analogue, may be a promising therapy at this stage of cardiomyopathy (CMP).

[Hemodynamic and clinical studies following injury of the arteries of the forearm]. / Hämodynamische und klinische Untersuchungen nach Verletzung von Unterarmarterien.

Forearm arterial injury usually does not lead to acute ischemia, but a functional deficit may develop. We tried to evaluate the need for two patent forearm arteries using rheological, Doppler sonographical and clinical parameters. Twenty-seven patients were examined after arterial and/or nerve injury in the forearm as well as six patients in whom a forearm flap was harvested. In seventeen patients both arteries were patent after primary reconstruction. Nine patients showed only one patent artery, while in the six patients with a forearm flap the radial artery was reconstructed in only one case. We found a decreased skin temperature in cases with artery and nerve injury. If both structures were reconstructed, the difference was not significant. The pressure of the finger collateral arteries and of the forearm arteries as well as the rheological investigation did not show any difference. The two-point discrimination, reflecting the nerve regeneration, was not affected, if one or two arteries had been reconstructed. Pain following exercise rarely occurred if both arteries of the forearm were patent. Because of the positive effect on skin temperature and of the reduced pain following exercise, reconstruction of both forearm arteries should be considered. Furthermore, the possibility of a subsequent arterial injury has to be taken into account.

Humoral regulation during cold-induced coronary arterial spasm.

Previous attempts to define the etiology of coronary arterial spasm have been focused on mechanisms such as autonomic nervous dysfunction and/or enhanced platelet activation. In the present study, humoral regulation was investigated in patients with vasospastic angina and scintigraphically documented transient myocardial perfusion abnormalities after a peripheral cold pressor test. Serial changes in angiotensin II, epi- and norepinephrine as well as thromboxane B2 (the stable derivate of thromboxane A2), and malondialdehyde were determined at baseline (I), immediately after 5 minutes cold water hand immersion (II), and following 10 minutes recovery (III). Angiotensin II and epinephrine remained unchanged during observation (I vs II, II vs III: P = NS). Norepinephrine was elevated after cold (I vs II: P less than 0.001) and normalized after 10 minutes (I vs III: P = ns). Thromboxane B2 and malondialdehyde increased continuously (I vs III: P less than 0.05 and I vs III: P less than 0.002, respectively). Further radiothin-layer chromatography results indicate an activation of platelet function during myocardial ischemia. Our results do not establish a cause-effect relationship but, together with other evidence, they may suggest that thromboxane A2 is unlikely to be the cause of spasm. It might, however, play an important role in the maintenance of vasoconstriction.

[Effects of omega-3-fatty acids on the prostaglandin system in healthy probands]. / Effekte von omega-3-Fettsäuren auf das Prostaglandinsystem gesunder Probanden.

Epidemiological comparisons of Greenland Eskimos and mainland Danes suggested that a diet rich in marine lipids mainly containing polyunsaturated fatty acids may be associated with a reduction in the incidence of occlusive vascular disease. Fish oils contain the Omega-3 polyunsaturated fatty acid eicosapentaenoate (timnodonic acid, EPA, 20:5n-3), which is incorporated into the platelet membrane after dietary intake instead of arachidonic acid (20:4n-6), the main substrate for prostaglandin synthesis. After incorporation of the fatty acids into the platelet membrane the overall effect of prostanoids with three double bonds derived from EPA proves to be less atherogenic. Since only TxA2 is a potent vasoconstrictor and platelet agonist whilst TxA3 is virtually biologically inert.

Platelet aggregation and platelet sensitivity-behaviour during normal and abnormal glucose tolerance testing.

Platelet aggregation response to ADP and platelet sensitivity to the antiaggregatory prostaglandin I2 (PGI2) were measured in 15 patients and 8 healthy volunteers undergoing intravenous glucose tolerance testing (GTT). Eight patients (5 female, 3 male, 44-57a) showed pathological GTT, in 7 patients (6 female, 1 male, 39-55a) and the healthy volunteers (6 female, 2 male, 24-39a) a normal response was monitored. After GTT in patients with pathological GTT the slope of the ADP-induced aggregation curve was diminished showing high variations, whereas the height of the aggregation curve remained unaltered. The platelet sensitivity to PGI2 was significantly (p less than 0.05) decreased during the performance of GTT and returned to prevalues until the end of GTT. In the patients as well as in the healthy volunteers with normal GTT no change could be monitored during the test. However, healthy volunteers showed significant (p less than 0.05) lower prevalues. The findings indicate, that an abnormal glucose tolerance is associated with a decreased platelet sensitivity to PGI2.

Beneficial effect of PGI2 on circulating endothelial cells.

Endothelial damage is an early event in atherogenesis. Recent data present evidence that the counting of circulating endothelial cells in human peripheral blood may provide reliable information about endothelial integrity. We therefore assessed the influence of PGI2 on the number of circulating endothelial cells in patients suffering from peripheral vascular disease. As cigarette smokers and patients with hyperlipoproteinemia show an increased number of circulating endothelial cells, they were excluded from this investigation. PGI2 causes a certain drop in circulating endothelial cells. In parallel, a prolongation in platelet half-life can be noted. This is most pronounced at a daily duration of infusion between 4 an 12 h. A shorter duration of PGI2 therapy is less effective in reducing circulating endothelial cells. All of the three different doses used, however, were equally effective. Placebo controls were ineffective. These findings indicate that PGI2 might exert a rather long-lasting beneficial action on endothelial integrity and the hemostatic balance.