Prostaglandin E1-therapy reduces circulating adhesion molecules (ICAM-1, E-selectin, VCAM-1) in peripheral vascular disease.

BACKGROUND: It has been postulated that adhesion molecules (AM) may be involved in development and progression of human atherosclerosis. We examined whether prostaglandin (PG) E1 affects circulating levels of the AM (ICAM-1, VCAM-1 and E-selectin) in peripheral vascular disease (PVD) patients. METHODS AND RESULTS: AM are significantly (p < 0.01) increased in PVD (n = 65) as compared to controls (n = 31). There was no influence of risk factors. 26 PVD-patients received 2 different schemes of PGE1-therapy (group A [n = 17]; 5 ng PGE1/kg/min x 6 h x 5 d x 4 wk; group B [n = 9]; 60 micrograms PGE1/2 h x 5 d x 2 wk). PGE1 decreases all the AM significantly (p < 0.01) using both therapeutic schemes. Stopping PGE1-therapy reverses values within about 4 weeks. Details on therapeutic regimens (dose, duration, route, etc.) and individual response still need to be assessed. CONCLUSION: Our results indicate that PGE1-treatment of PVD is associated with a significant benefit on circulating AM. These findings are in line with the described anti-inflammatory actions of PGE1 and may represent a further contributing factor to the great variety of beneficial actions of PGE1 on human atherosclerosis.

Successful eradication of Helicobacter pylori as determined by ((13))C-urea breath test does not alter fibrinogen and acute phase response markers.

In this study we examined in 100 patients testing positive for Helicobacter pylori infection whether successful eradication therapy with pantoprazole, clarithromycin, and metronidazole alters fibrinogen and other acute phase response markers. Of 100 patients, only 11 showed a fibrinogen level above 300 mg/dL. Successful eradication proven by the 13C-urea breath test does not alter acute phase response markers. These findings indicate that Helicobacter pylori infection is unlikely to affect atherosclerosis unfavourably via acute phase response.

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.

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.

Prostaglandin E1 decreases human arterial accumulation of radiolabeled apo B-containing lipoproteins in vivo.

OBJECTIVE: An increased apo B-containing lipoprotein influx and cholesterol ester accumulation in arteries are well-known events in human atherogenesis. In vitro and experimental animal studies have provided evidence of a beneficial effect of PGE1 on both vascular apo B-containing lipoprotein accumulation and cholesterol ester content. METHODS: We examined the effect of PGE1 (administered via an intravenous portable infusion pump at a rate of 5 ng PGE1 kg-1.min-1 for 5 days a week, 6 h daily, over a total of 5 weeks) in ten patients (eight males, two females) on 123I-apo B-containing lipoprotein accumulation into the large arteries in vivo. Apo B-containing lipoprotein isolation was carried out by immunoaffinity chromatography and radiolabeling with the iodine monochloride method. 123I-apo B-containing lipoprotein accumulation was imaged and quantified by means of special computer software before and after 5 weeks of PGE1 therapy. RESULTS: PGE1 led to a significant decrease in maximal arterial apo B-containing lipoprotein retention. The mean decrease in the carotid and femoral arteries in type I lesions amounted to between 16.9% and 30.4%, and in type II lesions between 22.4% and 30.7%, 20 h after injection of radiolabeled apo B-containing lipoprotein. The type of arterial apo B-containing lipoprotein kinetic curves, however, remained unchanged. CONCLUSION: These findings indicate that PGE1 decreases the apo B-containing lipoprotein influx in the large arteries and the vascular cholesterol content, suggesting that PGE1 may lead to regression of lipid-rich lesions in human in vivo.

Prostaglandin I2-mediated upregulation of 125I-LDL-receptor binding by isradipine in normo- and hypercholesterolemic rabbits in vivo.

The in-vivo low-density lipoprotein (LDL)-uptake by the liver was monitored during the initial 60 minutes after injection of radiolabelled LDL. LDL-uptake by the liver as evidenced by the liver/blood pool ratio in normocholesterolemic male New Zealand white rabbits (44.2 +/- 3.1% of whole body activity) was almost double as compared to the ones fed a 1% cholesterol enriched diet (22.5 +/- 3.3%). The blood disappearance of 125I-LDL was significantly faster in normocholesterolemic animals. A 4-week treatment with the dihydropyridine calcium channel blocker isradipine resulted in a significantly enhanced LDL-binding by the liver, both in normo- and hypercholesterolemic animals to a comparable extent. A concomitant acetylsalicylic acid (ASA) treatment completely abolished the benefit induced by isradipine while ASA alone was ineffective. Similarly, 125I-LDL disappearance from blood was improved by isradipine, while ASA neutralizes this effect. Again, ASA alone did not change the kinetics. Plasma cholesterol and high-density lipoprotein (HDL) cholesterol remained unchanged. Isradipine significantly enhanced vascular prostaglandin(PG)I2-generation while concomitant ASA treatment or ASA application alone almost completely depressed PGI2-formation. It is concluded that the improved LDL-binding by the liver is due to an enhanced PGI2-formation evoked by isradipine.

Prostaglandin E1 decreases circulating endothelial cells.

Prostaglandin E1 (PGE1) has been claimed to have cytoprotective effects and also to decrease thrombogenicity. The effect of intraarterial (i.a.) and intravenous (i.v.) administration of PGE1 on the number of circulating endothelial cells (CEC) was investigated in patients with peripheral vascular disease (PVD). Patients with hyperlipoproteinemia and also smokers exhibited higher numbers of CEC. PGE1 significantly (p < 0.01) decreased CEC. In parallel, plate let survival was prolonged (r = 0.82). This effect lasted for more than a month after stopping PGE1-therapy. The observed decrease in CEC reflects the decreased thrombogenicity and improved haemostasis achieved after PGE1.

Synergistic antiplatelet action of nitric oxide (NO) with PGD2 and its metabolite PGJ2--relevance for cerebral circulation?

The PGI2/NO axis is well accepted for its central regulatory role in maintaining haemostatic balance in large arteries. Earlier findings suggest that PGD2 may also play a role in haemostatic regulation of human cerebral circulation. We therefore wondered whether PGD2 and its metabolite PGJ2 synergise in-vitro with NO. We approached this question using platelets of ten healthy donors and ADP as aggregation-inducing stimulus. Both PGD2 and PGJ2 do inhibit ADP-induced platelet aggregation in a dose-dependent manner. Platelet aggregation findings demonstrate that PGD2 and NO synergise, as does the metabolite PGJ2. Our data are indicative that the PGD2/NO and, in less extent, PGJ2/NO synergism might be of special importance for the cerebrovascular haemostatic control.

A multicenter study using causal readings, self-recordings, and ambulatory blood pressure monitoring to assess isradipine effects. AMICUS Study Group.

The antihypertensive efficacy of isradipine has been widely studied. In most studies, however, blood pressure values were assessed by causal readings (CR) only. Furthermore, whether or not such blood pressure readings are sufficient proof of efficacy is still under discussion. Thus, a multicenter study was devised wherein blood pressure were recorded by CR, self-recordings, and noninvasive ambulatory monitoring (ABM). A total of 595 patients with mild-to-moderate hypertension were treated for 6 months starting with 1.25 mg of isradipine twice daily. If, after 4 weeks of treatment, CR-determined diastolic blood pressure (DBP) was still > 90 mm Hg, this dosage was doubled (n = 327) and, at week 8, pindolol at 5 mg or spirapril at 3 mg daily was added if necessary for blood pressure control. On the basis of CR, the results confirmed that low dosages of isradipine twice daily are safe and effective in the treatment of mild-to-moderate hypertension. The mean decrease in CR-determined blood pressure was 28.5/19.0 mm Hg at week 24, and the normalization rate (DBP < or = 90 mm Hg) for all patients treated was 78.2%. However, SR-determined blood pressure reduction was 20.0/13.0 mm Hg, with a normalization rate of 42%, whereas ABM-determined blood pressure reduction was 7.0/4.2 mm Hg. On the basis of ABM recordings, 66% of the patients had a DBP < 90 mm Hg on entry into the study and their blood pressures did not decrease with treatment. Thus, it appears that CR-determined blood pressures bias study results by including normotensives and thereby overestimating efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Isradipine decreases arterial thrombogenicity in rabbits. A morphometric and radioisotopic study.

The effect of isradipine, a calcium antagonist, on aortic and iliac wall thrombogenicity was examined in rabbits. After one week of dosing, the abdominal aortic and iliac artery endothelium was abraded using a Fogarthy catheter. One group of animals (n = 8) was dosed for one week with isradipine 0.3 mg/kg. A second group of animals received 10 mg acetylsalicylic acid (ASA)/kg daily in addition, while a third group received the vehicle only. Finally, a fourth group of animals (n = 8) was treated with ASA only. The percentage denuded surface covered with contact (unspread) platelets decreased significantly (p < 0.01) from 14.7 +/- 2.0 to 9.3 +/- 2.1 (6.2 +/- 0.8 to 3.7 +/- 0.4). The amount of contact and spread platelets was diminished from 84.9 +/- 5.6 to 71.4 +/- 4.4 (91.8 +/- 5.3 to 75.2 +/- 4.6). Platelet thrombi decreased from 7.4 +/- 0.9 to 4.6 +/- 1.4 (9.4 +/- 1.9 to 5.2 +/- 0.7) in the aortic and the iliac artery, respectively. In-platelet deposition decreased by 39.9 and 41.9%. Concomitant ASA therapy not only abolished the effect of isradipine but enhanced thrombogenicity, probably as a result of almost complete blockade of vascular PGI2-production.

Isradipine inhibits mitotic and proliferative activity in the arterial wall.

The anti-mitotic (3H-thymidine uptake quantified using autoradiography) and anti-proliferative (counting of activated smooth muscle cells on semithin sections) effects of the dihydropyridine calcium channel blocker isradipine (0.3 mg/kg) have been assessed in a rabbit arterial stress model. Isradipine caused a significant drop in both mitotic and proliferative activity. These effects were more pronounced by pretreatment (6 hours before lesion induction with desoxycorticosterone) with isradipine as compared to posttreatment (6 hours after experimental lesioning). The benefit induced by isradipine was abolished by aspirin treatment. In-vitro vascular prostacyclin formation and cholesterol content were not affected. These findings suggest that the anti-atherosclerotic action of isradipine on mitotic activity and cellular proliferation is mediated by a cyclooxygenase product, most likely via enhanced local vascular PGI2-synthesis.

Indication for antihypertensive treatment: superiority of ambulatory vs casual blood pressure measurement.

The antihypertensive effect of isradipine was studied in 45 patients with mild-to-moderate hypertension (mean age 59 years) using casual and ambulatory 24-h blood pressure measurement. Patients were included into the study according to their casual blood pressure. Isradipine was started at a dose of 1.25 mg twice daily for 4 weeks, and increased to 2.5 mg twice daily if casual blood pressure was not normalized. If necessary, 3 mg of spirapril, a new angiotensin-converting enzyme (ACE) inhibitor, (n = 1) or 5 mg of pindolol (n = 1) was added. The active-treatment period lasted 24 weeks. At the end of the therapy, casual blood pressure was significantly decreased (p < 0.001) from 173/103 to 150/86 mmHg, and mean ambulatory blood pressure, from 146/87 to 140/83 mmHg (p < 0.05). When patients were divided into three groups according to initial whole-day ambulatory blood pressure values (group I: < 140/90 mmHg; group II: > or = 140/90 mmHg; group III: > or = 140/<90 mmHg), no effect of treatment was detected in group I. However, whole-day blood pressure fell significantly (p < 0.001) in group II (155/96 vs 143/88 mmHg) as did systolic blood pressure (p < 0.01) in group III (150/83 vs 142/81 mmHg), whereas diastolic blood pressure remained unchanged. Thus, ambulatory blood pressure measurement may be superior to casual measurement in the decision-making process to treat hypertension, avoiding not only the phenomenon of 'white-coat hypertension', but also ineffective treatment. This conclusion, however, should be confirmed by prospective studies.

Isradipine decreases the entry of radioiodine-labelled low-density lipoproteins into the arterial wall.

Experimental studies have demonstrated that isradipine significantly decreases the entry of radioiodine-labelled (125I) low-density lipoproteins (LDL) into the aorta. This study aimed to investigate whether similar effects could be detected in humans as well. Twelve patients (nine men and three women, aged from 35 to 53 years), all of whom had both hyperlipoproteinaemia (either type IIa or type IIb; mean total cholesterol: 296 +/- 25 mg/dl; mean LDL cholesterol: 208 +/- 22 mg/dl) and mild-to-moderate hypertension [mean systolic blood pressure (SBP): 149 +/- 12 mmHg; mean diastolic blood pressure (DBP): 104 +/- 4 mmHg] received isradipine (2 x 2.5 mg). Autologous radiolabelled (123I) LDL was reinjected and a gamma camera used to study the LDL kinetics before (at 20 min, 2 h and 20 h) and after (at the same time intervals) treatment with isradipine. Of interest were those arterial regions that are typically sites of atherosclerotic lesions (carotid artery, femoral artery). Results revealed three different types of LDL kinetics which were not altered by isradipine treatment. The quantitative LDL entry, however, was reduced by at least 4.7% with a maximum of 23.5% (p < 0.01). Only five vascular sites with type III kinetics were detected. These data suggest that isradipine may induce functional regression of atherosclerotic lesions.

Isradipine increases platelet--low-density lipoprotein binding: evidence from ex-vivo studies in humans.

The effects of isradipine (2.5 mg twice daily) on platelet--radioiodine-labeled [123I] low-density lipoprotein (LDL) binding were measured in 16 hypertensive patients (mean age 46.2 +/- 10.7 years) with (cholesterol > 250 mg/dl; n = 8) and without (cholesterol < 200 mg/dl; n = 8) hypercholesterolaemia during 4 weeks of isradipine treatment after 4 weeks of pretreatment placebo followed by 2 weeks of post-treatment placebo periods. Radioligand LDL-binding studies revealed that isradipine induced a significant (p < 0.001) rise in maximum binding capacity (Bmax) from a mean of 1148.6 +/- 244.3 ng protein/10(9) platelets to a mean of 1262.3 +/- 204.1 ng protein/10(9) platelets [dissociation constant (Kd): 9.7 +/- 4.9 micrograms protein/ml before treatment vs 7.8 +/- 3.7 g protein/ml after treatment]. After the post-treatment placebo phase, both Bmax and Kd returned to baseline levels. When the hypercholesterolaemic patients were compared with the normocholesterolaemics, the former revealed a more pronounced increase in platelet [125I]-LDL-binding capacity. Correspondingly, the dissociation constant showed a significantly (p < 0.05) greater decrease. In accordance with these results, both total and LDL cholesterol were reduced after 4 weeks of therapy with significant (p < 0.03) rises through to the end of the post-treatment placebo period. It is suggested that the observed increase in high-affinity platelet--LDL binding with isradipine treatment reflects a state of decreased in-vivo platelet activation, an effect which may be of particular clinical value in hyperlipidaemic patients.

Influence of calcium antagonists on platelet function and vascular prostacyclin production.

It is suggested that calcium antagonists can counteract the process of atherogenesis by influencing different cellular mechanisms, for example, inhibiting cellular migration and proliferation, as well as by having beneficial effects on lipid metabolism and platelet function. In an assessment of the activity of different calcium antagonists in various platelet function tests and prostacyclin (PGI2) synthesis, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nitrendipine and verapamil were tested in vitro for their effects on adenosine diphosphate (ADP)- or collagen-induced platelet aggregation, malondialdehyde (MDA) formation and vascular PGI2 production. Nitrendipine, isradipine and nicardipine were shown to inhibit both ADP- and collagen-induced platelet aggregation at the lowest concentration (0.5 microgram/ml). The half-maximum inhibiting concentration (IC50) of isradipine (4.78 +/- 0.36 micrograms/ml for ADP-induced platelet aggregation) was significantly (p < 0.01) lower than the IC50 of all the other drugs. Nitrendipine, with an IC50 of 44.2 +/- 5.32 micrograms/ml, and nicardipine, with an IC50 of 46.74 +/- 3.83 micrograms/ml, were respectively the second and third most effective compounds. Formation of MDA was also inhibited the most by isradipine, which exerted its inhibitory properties at one-fifth the concentration needed with the other agents: the IC50 of isradipine was 0.98 +/- 0.16 microgram/ml, which was significantly different (p < 0.05) compared with the second most effective agent, verapamil, which had an IC50 of 14.92 +/- 3.78 micrograms/ml. In-vitro PGI2 production was stimulated the most by isradipine as well, producing a significant (p < 0.01) increase to 417.8 +/- 47.6 pg/mg tissue/h (control: 296.4 +/- 17.6 pg/mg tissue/h) at a concentration of 0.5 microgram/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive effect of isradipine on ambulatory and casual blood pressure.

The antihypertensive effect of isradipine was studied in 35 mild-to-moderate hypertensive patients (mean age 57 years) using casual and ambulatory 24-h blood pressure measurement. After the placebo phase, oral treatment was started with 1.25 mg isradipine twice daily for 4 weeks, which was increased to 2.5 mg twice daily if blood pressure was not normalized [in one patient, the new angiotensin-converting enzyme (ACE) inhibitor spirapril was added at a dose of 3 mg daily after 4 weeks]. The active-treatment period lasted 24 weeks. At the end of therapy, casual blood pressure decreased significantly (P < .001) from 174/103 to 151/86 mm Hg, and mean ambulatory blood pressure from 145/88 to 139/84 mm Hg (P < .05). The total number of hypertensive systolic and diastolic blood pressure values also decreased. When patients were divided into normotensives and hypertensives according to their initial ambulatory blood pressure, no effect of treatment was detected in the normotensive group. Casual blood pressure was higher than the 24-h ambulatory pressure.

Increase in in vivo low-density lipoprotein (LDL) receptor binding after PGE1 and 13,14-dihydro-PGE1 treatment in rabbits.

In a total of 48 male rabbits, the influence of PGE1 and its metabolite, 13,14-dihydro-PGE1, on the liver LDL receptor was examined in vivo. One-half of the animals were fed a 1% cholesterol-enriched diet for 4 weeks, and the other 24 animals received their normal chow. One-third of the animals in both groups received PGE1 (5 micrograms/kg i.v.), another 13,14-dihydro-PGE1 (5 micrograms/kg i.v.), and the third was a control group receiving placebo injections only. The LDL-receptor activity (total LDL uptake by the liver vs. blood activity) after injection of radiolabelled [125I]LDL and LDL disappearance from plasma were quantified. In the cholesterol-supplemented animals, the radioactive LDL uptake was significantly (p < 0.001) lower compared to the control group. Both PGE1 and 13,14-dihydro-PGE1 caused a comparable increase in LDL uptake, the extent being more pronounced in the hypercholesterolemic animals. LDL disappearance in normocholesterolemic animals was much faster than in cholesterol-fed animals. Both of the PGs caused a faster disappearance, the extent being comparable. As a mechanism of action, an induction of messenger RNA for the receptor protein by the prostaglandins is discussed. These results indicate a hypolipidemic action of PGE1 and its biologically active metabolite at the receptor level.